Slc25a21 in cisplatin-induced acute kidney injury: a new target for renal tubular epithelial protection by regulating mitochondrial metabolic homeostasis
Abstract Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial ca...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07231-2 |
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| Summary: | Abstract Acute kidney injury (AKI) is a significant global health issue, which is often caused by cisplatin therapy and characterized by mitochondrial dysfunction. Restoring mitochondrial homeostasis in tubular cells could exert therapeutic effects. Here, we investigated Slc25a21, a mitochondrial carrier, as a potential target for AKI intervention. Renal Slc25a21 expression is negatively associated with kidney function in both AKI patients and cisplatin-induced murine models. Sustaining renal expression of Slc25a21 slowed down AKI progression by reducing cellular apoptosis, necroptosis, and the inflammatory response, likely through its regulation of 2-oxoadipate conversion. Slc25a21 is highly expressed in proximal tubular epithelial cells, and its down-regulation contributes to compromised mitochondrial biogenesis and integrity, as well as impaired oxidative phosphorylation. Mechanistically, reduced Slc25a21 in AKI disrupts mitochondrial 2-oxoadipate transport, affecting related metabolites influx and the tricarboxylic acid cycle. These findings demonstrate a previously unappreciated metabolic function of Slc25a21 in tubular cells, and suggest that targeting mitochondrial metabolic homeostasis by sustaining Slc25a21 expression could be a potential novel therapeutic strategy for AKI. |
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| ISSN: | 2041-4889 |